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MnSOD deficiency has a differential effect on disease progression in two different ALS mutant mouse models
Author(s) -
Muller Florian L.,
Liu Yuhong,
Jernigan Amanda,
Borchelt David,
Richardson Arlan,
Van Remmen Holly
Publication year - 2008
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.21049
Subject(s) - sod1 , amyotrophic lateral sclerosis , mutant , sod2 , oxidative stress , biology , pathogenesis , mitochondrion , superoxide dismutase , microbiology and biotechnology , immunology , disease , endocrinology , pathology , medicine , genetics , gene
Mitochondrial dysfunction and oxidative stress are thought to participate in the pathogenesis of amyotrophic lateral sclerosis (ALS). The purpose of this study was to determine the effect of reduced mitochondrial antioxidant defense on lifespan and disease progression in two mouse models of familial ALS ( G93A and H46R/H48Q mutant lines) that represent pseudo‐wildtype and metal‐deficient ALS mutants, respectively. The metal‐deficient H46R/H48Q mutant differs from the G93A mutant in that it cannot bind copper in the active site and thus lacks SOD activity. We crossed each of these mutant lines with mice deficient in the mitochondrial matrix antioxidant enzyme MnSOD ( Sod2 +/− mice). In both high ( G93A 1Gur ) and low ( G93A DL ) copy G93A strains, MnSOD deficiency caused a decrease in lifespan that was associated with a reduced disease duration rather than earlier disease onset. In contrast, MnSOD deficiency had no effect on lifespan or disease parameters of H46R/H48Q mutant mice. MnSOD deficiency thus has a differential effect on disease progression in different mutant SOD1 ALS mouse models, suggesting that different ALS‐causing mutations in SOD1 result in disease progression by at least proximally different mechanisms/pathways. Muscle Nerve 38: 1173–1183, 2008